Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome

Abstract

Purpose To analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations. Methods Twenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11 , RAF1 , and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11 , RAF1 , SOS1 , KRAS , and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy. Results The mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11 , RAF1 , and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group. Conclusion The 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11 , RAF1 , and SOS1 groups.

Effectiveness of growth hormone therapy in children with Noonan syndrome

“…Numerous studies have reported increased height SDS and growth velocity with rhGH therapy [ 12 - 16 ]. Osio et al [ 17 ] reported improved final height outcomes in patients with NS, including a change in height SDS of 1.7 and mean height gain of 13 cm in boys and 9.8 cm in girls after 7.5 years of treatment.…”

“…Jeong et al [ 13 ] reported that the height SDS in patients without PTPN11 mutations was significantly greater than that in patients with PTPN11 mutations after 3 years of rhGH therapy. However, Jo et al [ 12 ] reported that the growth velocity in patients with PTPN11 mutations was greater than that in patients without mutations in NS-related genes. Malaquias et al [ 22 ] reported that patients without PTPN11 mutations showed a poor response to rhGH therapy compared to patients with PTPN11 mutations.…”

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height

“…There are a few studies that have reported long-term results on the efficacy of rhGH treatment in NS (34)(35)(36). Recently, in two complementary non-interventional studies, NordiNet ® IOS and ANSWER, it has been demonstrated that NS children treated with rhGH achieved significant height gain during the first 3 years of follow-up (37).…”

Correlation between genetic heterogeneity and variability for response to growth hormone in Noonan syndrome

“…Binder [11] demonstrated a trend toward a higher first-year growth rate in prepubertal NS children without the PTPN11 mutation. In this regard, the study of Jo et al [12] is considered valuable because it compared early GH effects in prepuberty between patients with and those without NS-causing gene mutations. The association between shortterm growth response and genotype seems unsuitable for an analysis of GH effect in NS [8,13].…”

“…Heterozygous mutations in more than 17 genes are known to underlie NS or NS-related disorders. In the study of Jo et al [12], the response to GH therapy of NS children in PTPN11, RAF1 , and SOS1 mutation groups were compared to those of NS patients in 5 genes ( PTPN11, RAF1, SOS1, KRAS , and BRAF ) undetected (FGU) group. There are several problems with organizing patients with NS without mutations in 5 genes into the FUG group, as patients in the FGU group may have other undetected NS-causing genes.…”